Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma.

Abstract

Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966-76. ©2016 AACR.

• Authors: Xiaoyun Dai, Kwang Seok Ahn, Ling Zhi Wang, Chulwon Kim, Amudha Deivasigamni, Frank Arfuso, Jae-Young Um, Alan Prem Kumar, Young-Chae Chang, Dhiraj Kumar, Gopal C Kundu, Junji Magae, Boon Cher Goh, Kam Man Hui, Gautam Sethi
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 12 Pg. 2966-2976 (12 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27765853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Alkenes
• Antibiotics, Antineoplastic
• Biomarkers
• Phenols
• STAT3 Transcription Factor
• Snail Family Transcription Factors
• Doxorubicin
• ascochlorin

Topics

• Alkenes (pharmacology)
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Biomarkers
• Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (drug therapy, genetics, pathology)
• Mice
• Phenols (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Snail Family Transcription Factors (genetics, metabolism)